US20130116324A1 - Pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune diseases containing ramalin - Google Patents

Pharmaceutical composition for the prevention or treatment of inflammatory diseases or immune diseases containing ramalin Download PDF

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US20130116324A1
US20130116324A1 US13/701,113 US201113701113A US2013116324A1 US 20130116324 A1 US20130116324 A1 US 20130116324A1 US 201113701113 A US201113701113 A US 201113701113A US 2013116324 A1 US2013116324 A1 US 2013116324A1
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ramalin
disease
inflammatory
pharmaceutical composition
immune
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Joung Han Yim
Il Chan Kim
Sung Gu Lee
Doc Kyu Kim
Se Jong HAN
Hyoung Seok LEE
Sung Jin Kim
Tai Kyoung Kim
Pil-Sung Kang
Heeyong Park
Ha Ju Park
Suhkneung Pyo
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Korea Ocean Research and Development Institute (KORDI)
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Assigned to KOREA OCEAN RESEARCH AND DEVELOPMENT INSTITUTE reassignment KOREA OCEAN RESEARCH AND DEVELOPMENT INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KIM, DOC KYU, LEE, SUNG GU, HAN, SE JONG, KANG, PIL-SUNG, KIM, IL CHAN, KIM, SUNG JIN, KIM, TAI KYOUNG, LEE, HYOUNG SEOK, PARK, HA JU, PARK, HEEYONG, PYO, SUHKNEUNG, YIM, JOUNG HAN
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Definitions

  • the present invention relates to the novel use of Ramalin for treatment of inflammatory disease or immune disease. More specifically, the present invention relates to a pharmaceutical composition for preventing and treating inflammatory disease or immune disease, which contains Ramalin having anti-inflammatory activity or a salt thereof, and a method of preventing or treating inflammatory disease or immune disease using the composition.
  • Inflammatory responses are defensive responses which are caused by various factors such as infection with pathogens or injury of tissue in the body and perform initial protective action to limit damage to infected or injured areas. In most cases, such inflammatory responses lead to the removal of pathogenic factors and the induction of adaptive immunity by the components of innate immunity (Hawiger J., Innate Immunity and Inflammation: A Transcriptional Paradigm. Immunologic Research. 23, pp. 99-109, 2001).
  • Rubors, tumors, calors, dolors and the like known to be accompanied by inflammation, are the results of continuous inflammatory responses, such as an increase in local blood flow and a decrease in local blood flow rate, which result from vasodilation caused by the action of inflammatory mediators and cytokines in the area of inflammation, an increase in the release of plasma components from blood vessels, which results from an increase in the permeability of blood vessels, an increase in the release of immune cells from blood vessels, which results from the adhesion of blood vessel endothelial cells to circulating immune cells, and an increase in migration to an infected area by chemotaxis (Gallo R L, Murakami M, Takaaki O, Zaiou M., Biology and clinical relevance of naturally occurring antimicrobial peptides.
  • inflammation-related vasodilation and an increase in the permeability of blood vessels are also attributable to histamines which are produced in some cells in response to tissue injury, and low-molecular-weight peptide kinins which are present in an inactivated state in blood and activated by tissue injury (Yamaki K, Thorlacius H, Xie X, Lindbom L, Hedqvist P, Raud J., Characteristics of histamineinduced leukocyte rolling in the undisturbed microcirculation of the rat mesentry. British J. Pharmacol. 123, pp. 390-399, 1998; Brocklehurst W E, Role of Kinins and Prostaglandins in Inflammation. Proc. Roy. Soc. Med. 64, pp. 4-6, 1971).
  • an acute inflammatory response occurs rapidly, is maintained for a short time and is accompanied by a systemic response known as the acute-phase response.
  • chronic inflammation can result continuous immune activation in connection with some diseases such as infection or autoimmune diseases, and the accumulation and activation of macrophages is the hallmark of chronic inflammation (Huang A L, Vita J A, Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation. Trends, Cardiovasc. Med. 16, p. 1520, 2006).
  • continuous chronic inflammatory responses can cause serious damage to host cells or tissue.
  • Inflammatory responses at the site of infection are initiated by the response of macrophages to pathogens. It is known that reactive oxygen species and reactive nitrogen species (e.g., NO), which are produced by macrophages activated by pathogens, inflammatory mediators such as prostaglandins and leukotrienes, and pro-inflammatory cytokines such as TNF- ⁇ , IL-6 and IL-8, are involved in inflammatory responses (Renauld J C, New insights into the role of cytokines in asthma. J. Clin. Pathol. 54, pp. 577-589, 2001; Blake G J, Ridker P M, Tumour necrosis factor- ⁇ , inflammatory biomarkers, and atherogenesis. Eur. Heart J. 23, pp.
  • reactive oxygen species and reactive nitrogen species e.g., NO
  • inflammatory mediators such as prostaglandins and leukotrienes
  • pro-inflammatory cytokines such as TNF- ⁇ , IL-6 and IL-8
  • NF- ⁇ B that is a transcriptional factor of genes related to the production of inflammatory mediators is very important in the inflammation-related action of macrophages. It was reported that inflammation-related genes, including inducible nitric oxide synthase (iNOS2), cyclooxygenase (COX-2), TNF- ⁇ , IL-6, IL-8 and the like, are transcribed by NF- ⁇ B in macrophages.
  • iNOS2 inducible nitric oxide synthase
  • COX-2 cyclooxygenase
  • TNF- ⁇ TNF- ⁇
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • Nitric oxide is produced from L-arginine by nitric oxide synthase (hereinafter referred to as NOS) in the macrophages of the human body (Kerwin, J. F. et al., J. Med. Chem., 38:4343, 1995).
  • NOS nitric oxide synthase
  • the NOS of the human body has three NOS isomers, including endothelial constitutive NOS (hereinafter referred to as ecNOS), neuronal constitutive NOS (hereinafter referred to as ncNOS) and inducible NOS (hereinafter referred to as iNOS).
  • ecNOS and ncNOS are expressed in endothelial cells and neuronal cells, respectively, and dependent on calcium and calmodulin
  • iNOS is highly expressed in various cells only when the cells are activated by lipopolysaccharide (hereinafter referred to as LPS) present in the cell membrane of pathogenic bacteria, cytokines such as IL-1 and TNF- ⁇ , and immune stimulants such as radiation, and iNOS is not dependent on calcium and calmodulin.
  • LPS lipopolysaccharide
  • NO functions as a defense against tumor cells and pathogenic bacteria at high concentration, and a low concentration of NO produced in blood vessel endothelial cells functions to regulate blood pressure, and NO produced in neuronal cells performs various physiological responses related to neurotransmitter function, learning, memory and the like.
  • Constitutive NOS plays an important role in maintaining the homeostasis of the human body, and NO produced by ecNOS acts in the blood vessel system to inhibit vasodilation and platelet adhesion or aggregation, and NO produced by ncNOS acts in the nerve system to increase long-term memory or acts as a neurotransmitter to cause melancholia and is involved in the mobility of the digestive tract or the erection of the penis.
  • NO produced by iNOS expression induced by specific cytokines or LPS is involved in inflammatory expression or host defense mechanisms.
  • the transcriptional factor NF- ⁇ B is activated in macrophages by the stimulation of endotoxin to induce iNOS expression, thereby increasing the production of NO (Butler, A. R., Chemistry & Industry, 16:828, 1995). It is known that when the expression of iNOS is induced by external stimulation of LPS, inflammation inducers radiation or the like, a large amount of NO is produced continuously for 4-6 hours to cause inflammatory responses in the human body.
  • NO synthesized by the expression performs antimicrobial action and antitumor action.
  • NO is produced in excessively large amounts, it causes inflammatory responses, such as arthritis and septicemia, tissue graft rejection, immune diseases such as autoimmune diseases and diabetes, and the death of neuronal cells.
  • iNOS activity inhibitors have high potential as agents for treating such diseases, and from this viewpoint, compounds that inhibit NO production caused by iNOS can be used as agents for treating various inflammatory diseases in the human body.
  • studies on materials that inhibit the production of NO have been conducted mainly on the development of materials that specifically inhibit the enzymatic activity of iNOS. Specifically, studies have been conducted on the development of derivatives of the precursor L-arginine, derivatives of L-citrulline, derivatives of amino guanidine, derivatives of isothiourea, etc., (Babu, B. R. B. and Griffith O. W., Current Opinion in Chemical Biology, 2:491, 1998).
  • Lichens are similar to non-flowering plants and are the symbiotic association of fungi (mycobionts) with algae and/or cyanobacteria (photobionts).
  • the fungi in lichens form thalli or lichen substrates containing typical secondary metabolites (Ahmadjin V., The lichen symbiosis , Wiley, New York, pp. 1-6, 1993). It is difficult to obtain sufficient amounts of natural lichen samples, and technology of cultivating large amounts of lichens is not known. For this reason, studies on lichens were relatively insufficient compared to studies on higher plants.
  • Ramalina terebrata is a lichen that grows naturally in the Antarctic King George Island can be easily collected from King George Island.
  • the present inventors previously isolated the novel compound Ramalin having excellent antioxidant activity (Korean Patent Application No. 2008-111021). However, there has been no report that Ramalin has anti-inflammatory activity.
  • the present inventors have examine the cellular immunity inhibitory activity of Ramalin by conducting comparative experiments in vitro and in vivo in order to determine the effect of Ramalin on the LPS-induced production of NO in mouse macrophage RAW264.7 cells, and as a result, have found that Ramalin has the effect of inhibiting inflammatory responses.
  • Ramalin of the present invention inhibited the mRNA expression of iNOS to significantly inhibit the production of NO, inhibited the activation of NF- ⁇ B, inhibited p38 MAPK, ERK1/2 and JNK signaling pathways, inhibited the expression of the LPS receptor TLR4, and showed excellent anti-inflammatory and immune regulatory effects in in vivo experiments, thereby completing the present invention.
  • the present invention provides a pharmaceutical composition for preventing or treating inflammatory disease or immune disease, which contains, as an active ingredient, Ramalin having a structure of the following formula 1 or a pharmaceutically acceptable salt thereof:
  • Ramalin functions to inhibit the expression of iNOS gene to inhibit the excessive production of nitric oxide (NO).
  • the inflammatory disease or immune disease may be atopic dermatitis, arthritis, urethritis, cystitis, arteriosclerosis, allergic disease, nasitis, asthma, acute pain, chronic pain, paradentitis, gingivitis, inflammatory bowel disease, gout, myocardial infarction, congestive heart failure, hypertension, angina pectoris, stomach ulcer, cerebral infarction, Down's syndrome, multiple sclerosis, obesity, diabetes, dementia, depression, schizophrenia, tuberculosis, sleep disorder, sepsis, a burn, pancreatitis, Parkinson's disease, stroke, brain damage caused by seizure, or autoimmune disease.
  • the composition may further contain a suitable carrier, excipient or diluent which is commonly used in preparation of pharmaceutical compositions.
  • the composition may be formulated or used in combination with one or more agents selected from the group consisting of anti-histamine agents, anti-inflammatory agents, anticancer agents and antibiotics.
  • the present invention also provides the use of Ramalin having a structure of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating inflammatory disease or immune disease.
  • the present invention also provides a method of preventing or treating inflammatory disease or immune disease using Ramalin having a structure of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for preventing or treating inflammatory disease or immune disease, the method comprising a step of treating (administrating) a subject with Ramalin having a structure of formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a functional food and functional cosmetic product for preventing or improving inflammatory disease or immune disease, which contain, as an active ingredient, Ramalin having a structure of formula 1.
  • FIG. 1 shows the results of measuring the level of nitrite in media for 24 hours after LPS treatment.
  • FIG. 2 shows the results of RT-PCR analysis conducted to examine the expression levels of iNOS mRNA and GAPDH mRNA as a control.
  • FIG. 3 shows the results of Western blot analysis conducted to examine the level of iNOS protein and the level of ⁇ -actin as a control.
  • FIG. 4 shows the results of measuring the surface expression level of TLR4 for 24 hours after LPS treatment.
  • FIG. 5 shows the results of RT-PCR analysis conducted to the expression levels of TLR4 mRNA and GAPDH mRNA as a control.
  • FIG. 6 shows the results of Western blot analysis conducted to examine the level of TLR4 protein and the level of ⁇ -actin as a control.
  • FIG. 7 shows the results obtained by transforming RAW 264.7 cells with a pGL3-NF- ⁇ B-Luc reporter plasmid and pCMV- ⁇ -gal, treating the cells with LPS for 4 hours and then measuring relative luciferase activities.
  • FIG. 8 shows the results of Western blot analysis conducted to measure the amount of p65 nuclear protein in order to analyze the translocation of NF- ⁇ B.
  • FIG. 9 shows the results obtained by pre-treating or not pre-treating cells with 10 ⁇ g/ml of Ramalin, treating the cells with 1 ⁇ g/ml of LPS for the indicated time, and then analyzing the cells by Western blot analysis with anti-I ⁇ B ⁇ antibody.
  • FIG. 10 shows the effect of Ramalin on the activation of p-p38, p-JNK and p-ERK in LPS-stimulated macrophages and shows the results obtained by pre-treating cells with Ramalin for 1 hour, treating the cells with LPS for 20 minutes and then analyzing the total cell lysate by Western blot analysis.
  • FIG. 11 shows the results of measuring the volume of rat foot edema induced by carrageenan and indicates that a group administered with Ramalin (100 mg/kg) showed an anti-inflammatory effect of about 50% after 6 hours compared to a control group administered with a vehicle and a positive control group administered with indomethacin (SigmaI-7378).
  • the present invention is directed to the novel use of a compound Ramalin having a structure of the following formula 1:
  • Ramalin of the present invention is a compound isolated from the Antarctic lichen Ramalina terebrata and having antioxidant activity.
  • the high-resolution ESI-MS of the Ramalin indicated that the Ramalin has a molecular weight of 254.1141 and is a compound having a molecular formula of as shown in formula 1.
  • the name “Ramalin” was given because it is a compound isolated from Ramalina terebrata.
  • Ramalin inhibits the expression of inducible nitric oxide synthase (iNOS) in the transcriptional stage to significantly inhibit the production of nitric oxide (NO), a key mediator of inflammatory responses, inhibits the phosphorylation of the inflammatory mediator NF- ⁇ B, inhibits p38 MAPK, ERK1/2 and JNK signaling pathways, and also inhibits the expression of the LPS receptor TLR4.
  • iNOS inducible nitric oxide synthase
  • NO nitric oxide
  • the present invention provides the use of Ramalin having a structure of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating inflammatory disease or immune disease.
  • the present invention is directed to a pharmaceutical composition for preventing or treating inflammatory disease or immune disease, which contains, as an active ingredient, Ramalin having a structure of formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of preventing or treating inflammatory disease or immune disease using Ramalin having a structure of formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method for preventing or treating inflammatory disease or immune disease, the method comprising a step of treating (administrating) a subject with Ramalin having a structure of formula I or a pharmaceutically acceptable salt thereof.
  • the treatment or administration may be performed in vivo or in vitro.
  • the inflammatory disease or immune disease may be atopic dermatitis, arthritis, urethritis, cystitis, arteriosclerosis, allergic disease, nasitis, asthma, acute pain, chronic pain, paradentitis, gingivitis, inflammatory bowel disease, gout, myocardial infarction, congestive heart failure, hypertension, angina pectoris, stomach ulcer, cerebral infarction, Down's syndrome, multiple sclerosis, obesity, diabetes, dementia, depression, schizophrenia, tuberculosis, sleep disorder, sepsis, a burn, pancreatitis, Parkinson's disease, stroke, brain damage caused by seizure, or autoimmune disease.
  • inflammatory disease refers to a disease caused by an inflammatory response induced by an external or internal material, and examples of inflammatory disease include neuroinflammatory diseases and arthritis.
  • immune disease refers to a disease caused by the excessive response of the immune system in the human body, and typical examples of immune disease include allergic diseases.
  • inflammatory disease is ultimately caused by the response of the immune system in the body, the term “inflammatory disease” and the term “immune disease” can be similar to each other in a broad sense, and thus are used interchangeably in the specification.
  • the pharmaceutical composition according to the present invention can be administered by various routes, including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardial, transdermal, subcutaneous, intraperitoneal, intranasal, gastrointestinal, local, sublingual and rectal routes.
  • the composition of the present invention is administered orally or parenterally.
  • the term “partenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, intra-articular, intra-synovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of suppositories for rectal administration.
  • the pharmaceutical composition of the present invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • the dose level of the pharmaceutical composition of the present invention will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the specific disease to be prevented or treated.
  • the pharmaceutical composition according to the present invention can be formulated in the form of pills, sugar-coated tablets, capsules, liquid, gel, syrup, slurry or suspensions.
  • the pharmaceutical composition may be formulated or used in combination with one or more drugs selected from the group consisting of anti-histamine agents, anti-inflammatory agents, anticancer agents and antibiotics.
  • the present invention is directed to a method for preventing or treating inflammatory disease or immune disease, the method comprising administering a pharmaceutical composition for preventing or treating inflammatory disease or immune disease, which contains, as an active ingredient, Ramalin having a structure of formula 1 or a pharmaceutically acceptable salt thereof.
  • the inventive pharmaceutical composition and preventing or treating method can be effectively used because they use Ramalin that is a natural material-derived compound having excellent anti-inflammatory activity and having no toxicity and side effects.
  • the present invention is directed to a functional food for preventing or improving inflammatory disease or immune disease, which contain, as an active ingredient, Ramalin having a structure of formula 1.
  • the functional food of the present invention can be used in various applications, including drugs, foods and beverages.
  • Examples of the functional food of the present invention include various foods, candies, chocolates, beverages, gums, teas, vitamin complexes, health supplement foods, and the like, and it can be used in the form of powders, granules, tablets, capsules or beverages.
  • the immune disease or inflammatory disease in the present invention may be atopic dermatitis, arthritis, urethritis, cystitis, arteriosclerosis, allergic disease, nasitis, asthma, acute pain, chronic pain, paradentitis, gingivitis, inflammatory bowel disease, gout, myocardial infarction, congestive heart failure, hypertension, angina pectoris, stomach ulcer, cerebral infarction, Down's syndrome, multiple sclerosis, obesity, diabetes, dementia, depression, schizophrenia, tuberculosis, sleep disorder, sepsis, a burn, pancreatitis, Parkinson's disease, stroke, brain damage caused by seizure, or autoimmune disease.
  • Ramalin which contained as an active ingredient in the functional food of the present invention has excellent anti-inflammatory activity.
  • Ramalin will exhibit excellent effects when it is used in foods.
  • the present invention is directed to a functional cosmetic product for preventing or treating inflammatory disease or immune disease, which contain, as an active ingredient, Ramalin having a structure of formula 1.
  • the functional cosmetic product of the present invention may be formulated as conventional emulsions and solubilized formulations.
  • the emulsion-type cosmetic formulations include milk lotion, cream, essence and the like, and the solubilized cosmetic formulations include skin lotion.
  • cosmetic formulations suitable for the present invention include solutions, gels, anhydrous solids or pastes, oil-in-water emulsions, suspensions, microemulsions, microcapsules, microgranules, ionic (liposomes) or non-ionic vesicular dispersions, creams, skin lotions, powders, ointments, sprays and concealing sticks.
  • foam formulations and aerosol formulations containing compressed propellants are contemplated as possible formulations.
  • the cosmetic product of the present invention may further comprise adjuvants such as any other components that are conventionally used in the cosmetic field.
  • adjuvants include fats, organic solvents, solubilizer, thickeners, gelling agents, softeners, antioxidants, suspending agents, stabilizers, foaming agents, aromatics, surfactants, water, ionic or non-ionic emulsifiers, fillers, and chelators, preservatives, vitamins, screening agents, humectants, essential oils, dyes, pigments, hydrophilic or lipophilic activating agents and lipid vesicles.
  • These adjuvants may be introduced in amounts that are conventionally used in the dermatological field.
  • the functional cosmetic product of the present invention particularly has an excellent anti-inflammatory effect, and thus can be effective used as a functional cosmetic product that alleviates the symptom of inflammation caused by atopic dermatitis, which is an inflammatory disease of the skin to which cosmetic products are applied, or a burn.
  • Ramalin contained as an active ingredient in the functional cosmetic product of the present invention has excellent anti-inflammatory activity.
  • Ramalin will exhibit excellent effects when used in cosmetic products.
  • a portion (5 g) of the water-soluble extract was then subjected to automated mild pressure liquid chromatography (MPLC) using a stepwise gradient solvent system of 0%, 20%, 40%, 60%, 80% and 100% methanol in water.
  • the used gradient solvent system was 0% methanol in water (containing 0.1% formic acid) over 10 min, 20% methanol over 20 min, and 100% methanol over 30 min.
  • the flow rate was 2 ml/min.
  • ESIMS electrospray ionization mass spectrometry
  • mice were cultured in RPMI 1640 medium (GIBCO, Grand Island, N.Y., US) supplemented with 2 mM L-glutamine, 100 IU/ml penicillin, 100 ⁇ l/ml streptomycin and 10% heat-inactivated fetal bovine serum (FBS: Carlsband, US).
  • FBS heat-inactivated fetal bovine serum
  • the macrophages were cultured in a 96-well tissue culture dish at a concentration of 1 ⁇ 10 5 cells/well, and treated with Ramalin for 2 hours in order to examine cytotoxicity.
  • the cell viability was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay which measures the mitochondrial activity of viable cells.
  • MTT formazan was quantified by measuring the optical density at 550 nm using a Molecular Device microplate reader (Sunnyvale, Calif., US).
  • the amount of nitrogen dioxide accumulated in the medium was determined by transferring 100 ⁇ l of the supernatant from each well into an empty well dish, adding 100 ⁇ l of Griess solution (a 1:1 mixture of 0.1% naphthylethylene diamine dihydrochloride in distilled water and 1% sulfanilamide in 5% H 3 PO 4 ) thereto, and then measuring the absorbance at 550 nm using a Molecular Device microplate reader (Sunnyvale, Calif., US).
  • the concentration of nitrogen dioxide can be calculated from a standard curve for nitrite (NaNO 2 ).
  • the level of nitrogen dioxide may be indicative of the amount of nitric oxide (NO).
  • RT-PCR cells were treated with LPS and Ramalin as described in Example 2, and then the total RNA of the cultured cells was collected using Trizol (Invitrogen, US). Then, the total RNA was amplified by Superscript one step RT-PCR using a PLATINUM Taq kit (Invitrogen, US). The PCR product was loaded onto 1.2% agarose gel which was then stained with EtBr.
  • GAPDH was used as a control.
  • the PCR amplification was performed using the following primer sequences: for iNOS-F, 5′-AGA CTG GAT TTG GCT GGT CCC TCC-3′(SEQ ID NO: 1); for iNOS-R, 5′-AGA ACT GAG GGT ACA TGC TGG AGC-3′ (SEQ ID NO: 2); for GAPDH-F, 5′-CCA TGG AGA AGG CTG GGG-3′ (SEQ ID NO: 3); for GAPDH-R, 5′-CAA AGT TGT CAT GGA TGA CC-3′ (SEQ ID NO: 4).
  • cells were treated with LPS and Ramalin as described in Example 2, washed twice with PBS (phosphate buffered saline), and then lysed in lysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP40, 100 ⁇ g/ml phenylsulfonyl fluoride, 2 ⁇ g/ml aprotinin, 1 ⁇ g/ml pepstatin, and 10 ⁇ g/ml leupeptin). Then, the cell lysate was kept on ice for 30 minutes and centrifuged at 15000 g at 40° C.
  • lysis buffer 50 mM Tris, pH 8.0, 150 mM NaCl, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP40, 100 ⁇ g/ml phenylsulfonyl fluoride
  • TLR4 (toll-like receptor 4) signaling is known to play a pivotal role in the induction of inflammatory responses, and LPS is a ligand that is recognized by TLR4.
  • LPS is a ligand that is recognized by TLR4.
  • Macrophage Raw264.7 cells were subcultured, and then seeded in a 96-well plate at a density of 1-4 ⁇ 10 4 cells/well and cultured. After 12 hours of culture, the cells were treated with 0.1, 1 and 10 ⁇ g/mL of Ramalin and incubated for 2 hours. The supernatant was removed from the cultured cells, which were then washed with d-PBS and treated with LPS (1 ⁇ g/mL). After 8 hours, the expression level of TLR4 on the cell surface was measured by an ELISA assay.
  • the cells were washed twice with d-PBS and incubated in 200 mL of blocking buffer (1% FBS in d-PBS) at room temperature for 30 minutes to induce non-specific binding.
  • the cells were washed three times with washing buffer) (0.05% Tween 20 in d-PBS), and 100 ⁇ L of a 1:500 dilution of primary antibody TLR4 in blocking buffer was added thereto and allowed to stand for 2 hours at room temperature.
  • the cells were washed five times with washing buffer, and 100 ⁇ L of a 1:1000 dilution of alkaline phosphatase-conjugated anti-rat secondary antibody in blocking buffer was added thereto and allowed to stand at room temperature for 1 hour, after which the cells were washed seven times with washing buffer. 100 ⁇ L of a peroxidase substrate was added thereto and incubated at room temperature for 30 minutes in the absence of light. The absorbance at 650 nm was measured using a microplate reader.
  • TLR4 mRNA and the level of TLR4 protein were measured as described in Example 3.
  • NF- ⁇ B is a transcriptional factor that is most important in the expression of iNOS.
  • Ramalin pretreatment on NF- ⁇ B the expression level of luciferase was analyzed.
  • One method for analyzing the expression of NF- ⁇ B is a luciferase assay.
  • the luciferase assay is a test method for determining the activation of a promoter. In the luciferase assay, the promoter region of a specific gene is ligated into a vector containing luciferase, and when the promoter is activated, light is emitted.
  • a suspension of cells (1 ⁇ 10 6 cells/mL) in a medium containing 10% FBS, penicillin (100 IU/mL) and streptomycin (100 mg/mL) was incubated in a 60 mm Petri dish, and the cells were stabilized for 24 hours. Then, the cells were treated with a transfection mixture containing the promoter region to be introduced and were incubated for 24 hours. Then, the cells were incubated under varying conditions. The supernatant was removed from the incubated cells which were then washed with d-PBS.
  • lysis buffer 25 mM Tris-phosphate, pH 7.8, 2 mM DTT, 2 mM 1,2-diaminocyclohexane-N,N,N,N′ tetracetic acid, 10% glycerol, 1% triton X-100, 1.25 mg/mL lysozyme, 2.5 mg/mL BSA
  • lysis buffer 25 mM Tris-phosphate, pH 7.8, 2 mM DTT, 2 mM 1,2-diaminocyclohexane-N,N,N,N′ tetracetic acid, 10% glycerol, 1% triton X-100, 1.25 mg/mL lysozyme, 2.5 mg/mL BSA
  • the p65 subunit of NF- ⁇ B is known to play an important role in the initiation of transcription of inflammatory genes.
  • the expression level of p65 subunit protein was analyzed by Western blot in order to examine the effect of Ramalin.
  • I ⁇ B ⁇ is an NF- ⁇ B inhibitor that usually binds to NF- ⁇ B to inhibit the activity of NF- ⁇ B, and LPS or IFN-gamma promotes the separation of I ⁇ B ⁇ so that NF- ⁇ B is activated.
  • the level of I ⁇ B ⁇ protein was analyzed for 60 minutes.
  • luciferase was measured by transfection and reporter gene assays. Specifically, RAW 264.7 cells (5 ⁇ 10 5 cells/ml) were plated in a 6-well dish and transfected with pGL3-NF- ⁇ B and a pCMV-beta-gal plasmid using LipofectAMINE Plus (Sigma). For transfection, a mixture of 0.5 ⁇ g pGL3-NF- ⁇ B and 0.2 ⁇ g pCMV-beta-gal in LipofectAMINE Plus solution was added to the cells, and after 4 hours, the cells were pretreated with Ramalin for 4 hours, and after 2 hours, the cells were treated with LPS.
  • LipofectAMINE Plus Sigma
  • the cells were lysed in 200 ⁇ l of lysis buffer (24 mM Tris-HCl (7.8 PH), 2 mM dithiotreitol, 2 mM EDTA, 10% glycerol and 1% Triton X-100), and then the luciferase activity of 10 ⁇ l of the cell lysate was analyzed.
  • the test for each of luciferase and beta-galactosidase was performed three times by three different persons, and then luciferase activity was normalized with beta-galactosidase activity.
  • luciferase activity increased by 1.5 times due to LPS treatment, but when Ramalin treatment was performed, there was no increase in luciferase activity.
  • p38 MAPK, ERK1/2 and JNK kinase pathways are known as signaling stages that regulate the intermediate stage of inflammatory responses.
  • the expression levels of p38 MAPK, ERK1/2 and JNK were analyzed in order to examine the effect of Ramalin pretreatment.
  • This Example was performed in the same manner as Example 3, and the analysis of the levels of the proteins was performed by Western blot analysis in the same manner as Example 3.
  • the levels of p38, ERK and JNK proteins did not change regardless of Ramalin pretreatment, but the levels of p-p38, p-ERK and p-JNK, which are phosphorylated forms, decreased in a manner dependent on the concentration of Ramalin used to pre-treat the cells. This suggests that Ramalin inhibits the phosphorylation of each of the proteins, thereby inhibiting inflammatory responses.
  • Example 7 the effects of Ramalin pretreatment were analyzed in vitro.
  • Example 7 a test was performed using living rats in order to examine Ramalin actually has an anti-inflammatory effect.
  • rats were administered with each of a vehicle (control), 50 mg/kg of Ramalin, 100 mg/kg of Ramalin and indomethacin (anti-inflammatory agent, positive control), and then inflammatory responses in the rats were induced using carrageenan that is a kind of IDS, and the anti-inflammatory effect of Ramalin was evaluated based on the rate of increase in the volume of foot edema.
  • a pharmaceutical composition for preventing or treating inflammatory disease or immune disease which contains, as an active ingredient, Ramalin having a structure of the following formula 1 or a pharmaceutically acceptable salt thereof:
  • Carrageenan used in the test was purchased from Sigma (c-1867, CAS No.: 9000-07-1, EC No.: 232-524-2), and particularly a mixture of kappa-carrageenan and lambda-carrageenan was used.
  • Carrageenan is used as a food additive for increasing the stickiness, viscosity and emulsion stability of foods. In addition, it is used as a thickener, a gelling agent, a stabilizer or the like. Carrageenan is obtained by extracting seaweeds, including Chondrus sp., Eucheuma sp., Gigartina sp., Hypnea sp.
  • Iridaea sp. which are red algae known as Irish mosses, with water or hot alkaline aqueous solution, and purifying the extract, and the main components thereof are i(iota)-carrageenan, ⁇ (kappa)-carrageenan, and ⁇ (lambda)-carrageenan.
  • lambda-carrageenan (about 1-2%) is used as an edema-inducing material in inflammation-related animal tests.
  • the rats used in the test were male Sprague-Dawley rats (150-200 g, younger than 6 weeks) and purchased from Daehan Bio Co., Ltd. (Korea). The animals were maintained in the laboratory in accordance with internationally accepted principles for laboratory animal use and care.
  • the carrageenan used was a mixture of kappa-carrageenan and lambda-carrageenan and purchased from Sigma (USA), and the indomethacin used was also purchased from Sigma (USA).
  • Ramalin was used as a solution in 500 ⁇ l of saline at concentrations of 50 mg/kg and 100 mg/kg, the vehicle used was saline, and indomethacin was used as a solution in 500 ⁇ l of saline at a concentration of 10 mg/kg.
  • Each of Ramalin, the vehicle and indomethacin was administered to each rat, and after 1 hour, 100 ⁇ l of 1% carrageenan in saline was injected subcutaneously into the hind feet of the rats. Then, the thickness of the foot of each rat was measured for 6 hours, and the rate of increase in the volume of edema was determined. The results of the measurement are shown in FIG. 11 . At each point of time, three measurements were obtained and averaged.
  • the rat administered with 100 mg/kg of Ramalin showed a high anti-inflammatory effect and a significant difference in edema volume from the control group administered with the vehicle. This suggests that pretreatment with Ramalin significantly inhibit inflammatory responses.
  • the present invention provides a pharmaceutical composition containing Ramalin as an active ingredient.
  • the pharmaceutical composition shows an excellent effect of inhibiting the production of nitric oxide (NO) by inhibiting the production of iNOS, compared to conventional pharmaceutical compositions.
  • the pharmaceutical composition of the invention has the effect of treating inflammatory disease or immune disease by inhibiting excessive inflammatory responses and immune responses and can be used in functional foods and functional cosmetic products.

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